Monogenic Hypertension

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2 Monogenic HypertensionHT is a major public-health problemMolecular pathogenesis in most patients remains poorly understandGenetic factors …known to play a role in determining inter-individual variation in BP.

3 Monogenic HypertensionThere are mutations and polymorphisms that altering BP in humanAll the gene are involve directly or indirectly in control of Na reabsorptionMutations have been found in monogenic hypertension diseases that cause disorders of BP regulation

6 Glucocorticoid-remediable aldosteronism (GRA)AD monogenic HTResults from a chimeric gene product that place 18-hydroxylase (Aldosterone synthase) under control of ACTH promoterACTH-regulated 18-hydroxylase activity is aberrantly expressed in Zona fasciculata and acts upon control to form 18-hydroxy cortisol and 18-oxocortisol

7 AldosteroneAdrenal hormones are synthesized in different areas of adrenal cortexZG…AldosteroneZF…Glucocorticoid (cortisol)ZR…Androgen,estrogenZG…well adapted for aldosterone productionlow conc of 17-alpha hydroxylasefinal step in conversion of corticosterone to aldosterone

12 GRA and Pregnancy GRA not appeared to more prone to pre-eclampsiaGRA…chronic HT, increased risk of exacerbation of HT during pregnancyCesarean section rate > general and other obstetrics…2 foldsWycoff JA et al. Hypertension, 2000

16 AMEResembles the syndrome observed in persons integrity large amounts of licoriceVolume expansionSalt-sensitive HTHypokalemic metabolic alkalosisLow renin-Low aldosteroneHT respond to thiazide or spironolactone but no aldosterone and abnormal steroid products in urine

17 AME Palermo et al. ( NEJM, 1998 )Resolution of AME syndrome after KT in 38 year old womanAbnormal ratio of reduced metabolite of cortisol/cortisonr in urine was not correctedRatio of urinary free cortisol to cortisone was corrected and correlated with the resolution of the syndrome

33 Pregnancy in MRL810 2 affected women and 5 pregnantsSevere maternal HT, hypokalemia, hyperkaliuriaTermination of pregnancy or early deliveryNo other signs of pre-eclampsiaSupport of in-vitro finding that progesterone agonized MRL810

34 Progesterone-induced Activation of MRL810Require a novel helix3/helix5 interactionS810 on helix 5 was near alanine 773 (A773) on helix 3 but distance is too great for stabilizing effectWhen L810 is substituted, longer non-polar leucine side chain come into close contact with A773

35 Progesterone-induced Activation of MRL810How does this interaction allow progesterone-mediated activation of MR?Progesterone distinguished from MR agonists by absence of C-21 hydroxyl groupC-21 hydroxyl group form hydrogen bond with carbonyl group of asparagine 770 (N770) on helix 3…necessary for aldosterone-induced activation of MRIn MRL810 …novel interaction of A773 with L810 replace this function

37 Autosomal-dominant HT with brachydactylyFirst described bt Bilginturan et al. In 1973Dramatic increase in BP with age and die of stoke before age 50Map the gene to 12pPRA and aldosterone are normalNot salt-sensitiveNormal RAAS and catecholamine response